The goal of this proposal is to establish how endolymph composition and volume are regulated. Lack of knowledge in this area severely limits our understanding of disease processes of the inner car, such as Meniere's disease and perilymph fistula. For a number of years, we have pioneered the development of novel techniques to study inner ear fluids. Markers are iontophoresed, without volume disturbance, into the inner ear fluids and their movements monitored by ion-selective microelectrodes. These techniques have allowed the cross-sectional area and longitudinal movements of cochlear fluids to be accurately quantified in vivo. For some time, we have known that in the normal cochlea, longitudinal movements of cochlear fluids are extremely slow. We have now found that when endolymph volume is disturbed, longitudinal movements do occur which make a significant contribution to the ionic changes in endolymph. The first aim of this project is to characterize the dependence of endolymph area changes and longitudinal movements on mechanical factors, such as pressure and volume disturbances. We will then assess whether or not pharmacological manipulations of ion transport processes in the cochlea result in area or flow changes. Comparable measures will be made in animals in which the endolymphatic sac has been ablated, to assess the role of this structure in endolymph volume regulation. The pathophysiology of the initial stages of hydrops development will be investigated in detail. In addition, magnetic resonance (MR) microscopy will be used to generate accurate 3-D reconstructions of the cochlear fluid spaces under a variety of experimental conditions. These anatomic data will provide the basis for numeric models of homeostatic processes in the cochlear fluids, which will be used to optimize experimental design and to generate accurate quantitative interpretation of findings. We will correlate anatomic measures, physical measures of flow and area, and chemical measures of electrolyte composition with measures of cochlear function. Only by understanding the relationships between mechanical, chemical and physiological processes, can we hope to understand how endolymph volume is regulated and how disturbances of volume can be treated in patients.